The human estrogen receptor (ER) is a key transcription regulator in breast cancer biology. However the precise mechanism of ER action is not completely understood. Emerging evidence suggests that ER action is complex and requires functional interactions with coregulators. As a modulator of ER functions, coregulators are likely to play a role in breast cancer progression. There is a critical need to understand the role of ER coregulators in the initiation and progression of breast cancer and in the development of therapy resistance and metastasis. Our long term goal is to discover the role of ER coregulators in breast cancer progression and therapy resistance and to identify key ER coregulators that serve as alternative targets for current endocrine therapies. Our recent studies showed that PELP1 is a novel proto-oncogene that participates in ER genomic actions and nongenomic actions and its expression is deregulated in breast tumors. The objective of this application is to characterize the mechanisms by which ER coregulator PELP1 contributes to breast cancer progression, metastasis and to validate ER-PELP1 axis as a potential target for diagnosis and therapeutic intervention. Our central hypotheses are that ER coregulator PELP1 is a proto- oncogene, plays a critical role in the ER mediated chromatin modifications and cell cycle progression, its deregulation confer a growth advantage to breast epithelial cells and consequently, contribute towards malignant progression, metastasis and resistance to hormonal therapy. To investigate these hypotheses, in Aim 1, we will define the role of PELP1 in histone modifications and epigenetic code at the ER target genes. In aim 2, we will elucidate the mechanisms by which PELP1 promote E2 mediated cell proliferation, cell cycle progression and characterize the role of PELP1 in histone biosynthesis. In aim 3, we wil establish the mechanism and significance of PELP1-nongenomic signaling in ER therapy resistance. In aim4, we will determine the role of PELP1 in metastasis and evaluate its prognostic value in metastatic breast cancer. We will test these aims using molecular biology, proteomics, epigenetic and ChIP methodology and by using novel in vitro and in vivo models, and IHC studies using tumor arrays. Our proposed research is significant because of the novelty of the concepts involving PELP1 and findings from the proposed studies will define the role(s) of PLEP1 as a critical proto-oncogene of breast cancer progression by coupling ER with epigenetic modulators. In addition, this proposal establishes the role of ER-PELP1 axis in metastasis and hormonal therapy resistance and thus provide novel target for combination therapies to treat metastatic and advanced breast tumors. Understanding the key ER coregulators and their signal transduction mechanism will be a step forward for developing strategies for the next generation of advances in anti-estrogenic therapies.